CACH2; CACN2; CACNL1A1; CCHL1A1; CaV1.2; LQT8; TS
The CACNA1C gene is associated with autosomal dominant Timothy syndrome (TS), also known as long QT syndrome (LQTS), type 8 (MedGen UID: 331395), and short QT syndrome (SQTS) (MedGen UID: 378835). The CACNA1C gene has also been associated with a combination of LQTS, hypertrophic cardiomyopathy (HCM) and congenital heart defects (PMID: 26253506). Additionally, the CACNA1C gene has preliminary evidence supporting a correlation with autosomal dominant Brugada syndrome (PMID: 17224476).
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Pathogenic CACNA1C variants cause 100% of cases of Timothy syndrome, a subtype of LQTS, although they are a rare cause of LQTS overall. CACNA1C is also associated with an unknown percentage of clinical cases of SQTS and BrS.
The CACNA1C gene encodes the alpha-1 C subunit of a voltage-dependent calcium channel. Calcium channels control the flow of calcium ions in cardiac muscle. The electrical activity of cardiac muscle is controlled by the movement of potassium, sodium and calcium ions across cardiac muscle cell membranes. Mutations in genes that encode subunits of cardiac calcium channels are known to cause inherited cardiac arrhythmias.
The CACNA1C gene is associated with autosomal dominant Timothy syndrome, also known as long QT syndrome, type 8 (MedGen UID: 331395), Brugada syndrome (MedGen UID: 395633), and short QT syndrome (MedGen UID: 378835). The CACNA1C gene has also been associated with a combination of LQTS, hypertrophic cardiomyopathy (HCM), and congenital heart defects (PMID: 26253506).
Timothy syndrome is a multisystem disorder primarily involving the heart with a combination of other physical findings. The heart involvement in Timothy syndrome includes very early onset abnormal heart rhythms that can develop in the setting of a very prolonged QTc interval and heart block on electrocardiogram (ECG/EKG). In addition to electrical involvement of the heart, congenital structural heart disease is also a common feature of Timothy syndrome. The group of physical findings associated with Timothy syndrome include webbing of the fingers and toes (syndactyly) and distinctive facial features. Recurrent infections, low blood sugar, developmental delays, and autism spectrum disorders have also been associated with Timothy syndrome. Timothy syndrome has been reported to result from a few specific gain-of-function genetic changes and is an autosomal dominant, typically de novo, condition. There have been cases of siblings having Timothy syndrome due to suspected germline mosaicism.
Long QT syndrome (LQTS) is a cardiac arrhythmia condition that primarily affects the electrical system of the heart. LQTS is defined by a prolonged QTc interval and T wave abnormalities on an ECG without the presence of any known structural heart disease. Individuals with LQTS can develop a specific abnormal heart rhythm called Torsade de pointes (TdP). Disruption of the CACNA1C product ion channel in a gain-of-function manner may lead to a predisposition to develop LQTS.
Brugada Syndrome (BrS) is another cardiac arrhythmia condition that primarily affects the electrical system of the heart. BrS is defined by characteristic ST-segment elevations on an ECG. These ST-segment elevations are seen in certain areas of the ECG (leads V1-V3). BrS is associated with genetic changes in CACNA1C that cause a loss-of-function to the gene product. BrS exhibits reduced penetrance, meaning not everyone who inherits a predisposition to develop BrS will go on to manifest symptoms or have an abnormal resting ECG/EKG.
Short QT syndrome (SQTS) is also a cardiac arrhythmia condition that primarily affects the electrical system of the heart. SQTS is defined by a shortened QTc interval on an ECG. Individuals with SQTS can develop irregular and rapid heart rhythms initiating from the top (atrial) or bottom (ventricular) chambers of the heart. CACNA1C-related SQTS is associated with loss-of-function variants.
The abnormal heart beats in the above arrhythmia conditions can lead to palpitations, dizziness (pre syncope), fainting (syncope), seizure-like activity and, in some cases, sudden cardiac arrest/death including sudden infant death syndrome (SIDS). BrS is also associated with sudden unexpected nocturnal death syndrome (SUNDS) in individuals of Southeast Asian ethnicity. Symptoms can present in both children and adults and may be triggered by homeostatic imbalance and/or the use of certain medications.
In their description of CACNA1C-related conditions, Bozcek, et al, 2015 expands the phenotype to include hypertrophic cardiomyopathy (HCM) and congenital heart defects (CHD). HCM is a disorder involving the heart muscle. Hypertrophy refers to the thickening of the lower left (ventricular) heart muscle that occurs over time leading to the clinical symptoms of cardiac arrhythmias. CHDs are problems with the structural heart development before birth that disrupt the normal flow of blood and can affect the interior walls, valves, or connecting vessels of the heart. The group labeled this phenotype as cardiac-only Timothy syndrome resulting from p.Arg518His.
The CACNA1C gene encodes a calcium channel known as CaV1.2 which plays a key role in a cell’s ability to generate and transmit electrical signals. CaV1.2 channels are found in many cell types and appear to be particularly important for the normal function of heart and brain cells. In the heart, CaV1.2 channels open and close at specific times to control the flow of calcium and help maintain the heart’s normal rhythm. The role of CaV1.2 in the brain and in other tissues is less clear (National Library of Medicine. Genetics Home Reference. CACNA1C. https://ghr.nlm.nih.gov/gene/CACNA1C. Accessed November 2016).
Pathogenic variants in CACNA1C have autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing that variant on to their offspring. In the case of Timothy syndrome pathogenic variants are typically de novo although there have been cases of siblings having Timothy syndrome due to suspected germline mosaicism. CACNA1C pathogenic variants exhibit reduced penetrance and variable expression, meaning not everyone who inherits a predisposition to develop cardiac arrhythmia will go on to manifest symptoms or have an abnormal result on ECG/EKG analysis. Penetrance and variable expressivity have not been well studied in Timothy syndrome, although it has been reported that penetrance of Timothy syndrome causing variants is high.
Timothy syndrome is managed symptomatically since clinical experience with Timothy syndrome is scarce. Respiratory infections are managed with standard treatments of antibiotic and steroid therapy and syndactyly is usually surgically released. Surveillance also includes ongoing monitoring for hypoglycemia. Anesthesia is also known to trigger arrhythmia and surgical procedures should be performed under close cardiac monitoring. Additional cardiac manifestation management recommendations are as below.
Arrhythmias are recommended to be managed depending on clinical presentation with options including lifestyle modification, medication, surgical, and device therapy. Genetic testing may help elucidate specific triggers such as swimming or startling.
Hypertrophic cardiomyopathy (HCM) is recommended to be managed by a combination of lifestyle modification, medication, surgical and device therapy, and heart transplantation. Other natural sequelae of HCM, such as atrial fibrillation and heart failure, should be treated according to symptomatic recommendations. Pregnant women with HCM are recommended to receive increased fetal cardiac surveillance, genetic counseling, and evaluation for increased risk to the pregnancy. It is recommended that management decisions be made based on clinical presentation, symptoms, and family history as well as appropriate sudden cardiac death (SCD) risk stratification.
There are many different types of congenital heart defects (CHDs) and management and treatment should follow clinical evaluation and symptoms. Some CHDs are asymptomatic and require no intervention or medical therapy. For those CHDs that do require management, recommendations can include medication, surgical treatment, device therapy, prophylactic antibiotics, exercise modification, and continued clinical follow-up evaluations. Women considering pregnancy should be evaluated prior to conception for potential increased physical risk during pregnancy and heritability of their CHD.
Review date: January 2017
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
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